Retinoic acid post consolidation therapy for high-risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation

Peinemann, Frank; Dalen, Elvira C. van; Kahangire, Doreen A; Berthold, Frank

doi:10.1002/14651858.cd010685.pub2

Cited by 27 publications

(20 citation statements)

References 98 publications

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“…It may be better to target several critical basic biologic pathways in neuroblastoma tumor cells that are distinct from normal cells. The use of differentiating therapy with retinoic acid post autologous stem cell transplant has become standard of care and is an example of the success associated the use of an agent which likely affects several targets [6, 7]. The development of new therapies such as retinoic acid has occurred in minimal residual disease (consolidation/maintenance) since rates of complete remission in induction approach 100 % after intensive chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Treatment of a chemoresistant neuroblastoma cell line with the antimalarial ozonide OZ513

et al. 2016

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BackgroundEvaluate the anti-tumor activity of ozonide antimalarials using a chemoresistant neuroblastoma cell line, BE (2)-c.MethodsThe activity of 12 ozonides, artemisinin, and two semisynthetic artemisinins were tested for activity against two neuroblastoma cell-lines (BE (2)-c and IMR-32) and the Ewing’s Sarcoma cell line A673 in an MTT viability assay. Time course data indicated that peak effect was seen 18 h after the start of treatment thus 18 h pre-treatment was used for all subsequent experiments. The most active ozonide (OZ513) was assessed in a propidium iodide cell cycle flow cytometry analysis which measured cell cycle transit and apoptosis. Metabolic effects of OZ513 in BE (2)-c cells was evaluated. Western blots for the apoptotic proteins cleaved capase-3 and cleaved PARP, the highly amplified oncogene MYCN, and the cell cycle regulator CyclinD1, were performed. These in-vitro experiments were followed by an in-vivo experiment in which NOD-scid gamma immunodeficient mice were injected subcutaneously with 1 × 106 BE (2)-c cells followed by immediate treatment with 50–100 mg/kg/day doses of OZ513 administered IP three times per week out to 23 days after injection of tumor. Incidence of tumor development, time to tumor development, and rate of tumor growth were assessed in DMSO treated controls (N = 6), and OZ513 treated mice (N = 5).ResultsIt was confirmed that five commonly used chemotherapy drugs had no cytotoxic activity in BE (2)-c cells. Six of 12 ozonides tested were active in-vitro at concentrations achievable in vivo with OZ513 being most active (IC50 = 0.5 mcg/ml). OZ513 activity was confirmed in IMR-32 and A673 cells. The Ao peak on cell-cycle analysis was increased after treatment with OZ513 in a concentration dependent fashion which when coupled with results from western blot analysis which showed an increase in cleaved capase-3 and cleaved PARP supported an increase in apoptosis. There was a concentration dependent decline in the MYCN and a cyclinD1 protein indicative of anti-proliferative activity and cell cycle disruption. OXPHOS metabolism was unaffected by OZ513 treatment while glycolysis was increased. There was a significant delay in time to tumor development in mice treated with OZ513 and a decline in the rate of tumor growth.ConclusionsThe antimalarial ozonide OZ513 has effective in-vitro and in-vivo activity against a pleiotropic drug resistant neuroblastoma cell-line. Treatment with OZ513 increased apoptotic markers and glycolysis with a decline in the MYCN oncogene and the cell cycle regulator cyclinD1. These effects suggest adaptation to cellular stress by mechanism which remain unclear.

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Section: Introductionmentioning

confidence: 99%

Treatment of a chemoresistant neuroblastoma cell line with the antimalarial ozonide OZ513

et al. 2016

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“…Regarding overall and event-free survival there was no clear evidence in favor of either treatment group. Thus, the effects of isotretinoin therapy in patients with high-risk neuroblastoma seem to require further evaluation [12].…”

Section: Discussionmentioning

confidence: 99%

“…Tretinoin [(all-transretinoic acid (ATRA)] is the all-trans isomer of isotretinoin (13-cisretinoic acid, 13-cis-RA; Figure 1a); both represent metabolically active derivatives of vitamin A and are utilized in the fields of oncology and dermatology [1][2][3][4][5][6][7]. Tretinoin is systemically applied to patients with acute promyelocytic leukemia (APL) for induction of remission [8][9][10][11][12][13][14][15]. Isotretinoin is used in children with medium and high risk neuroblastoma; in vitro, therapy results in decreased cell proliferation and reduced expression of MYCN proto-oncogene protein [16][17][18][19].…”

Section: Contextmentioning

confidence: 99%

Toxic Optic Neuritis due to Isotretinoin in a Child with Neuroblastoma: A Case Report

Stächele¹,

Kokoschka²,

Toepfner³

et al. 2015

J Clin Toxicol

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Retinoids, namely tretinoin and isotretinoin, are metabolically active derivates of vitamin A and used as therapeutic agents. Tretinoin is part of the standard therapy for patients with acute promyelocytic leukemia. Isotretinoin is applied to children with medium and high risk neuroblastoma. Further, both isomers are frequently administered to patients with acne and other skin or mucosal disorders.Isotretinoin usage in dermatology has been associated with several ocular side effects. We report on the first pediatric patient with neuroblastoma who suffered from acute transient bilateral vision loss due to optic neuritis induced by systemical administration of isotretinoin. Therefore toxic optic neuritis needs to be considered as a potential adverse effect of isotretinoin therapy and weighed carefully against therapeutic benefits.By quantum mechanical calculations it could be shown that 13-cis/trans-isomerism of tretinoin has only minor influence on the molecular shape and electrostatic potential suggesting that the biochemical interactions as well as adverse effects for tretinoin and isotretinoin might be similar.

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“…Studies of 13-cis-RA as postconsolidation therapy after bone marrow transplantation are promising, but lack statistical power to definitively say whether or not it is effective in high-risk neuroblastoma. 87 …”

Section: Targeted Therapy For Neuroblastoma: a Developmental Neurobiomentioning

confidence: 99%

The “neuro” of neuroblastoma: Neuroblastoma as a neurodevelopmental disorder

Ratner

Brodeur

Dale

et al. 2016

Annals of Neurology

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Neuroblastoma is a childhood cancer derived from cells of neural crest origin. The hallmarks of its enigmatic character include its propensity for spontaneous regression under some circumstances and its association with paraneoplastic opsoclonus, myoclonus, and ataxia. The neurodevelopmental underpinnings of its origins may provide important clues for development of novel therapeutic and preventive agents for this frequently fatal malignancy and for the associated paraneoplastic syndromes.

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Retinoic acid post consolidation therapy for high-risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation

Abstract: Retinoic acid post consolidation therapy for high-risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation.

Cited by 27 publications

References 98 publications

Treatment of a chemoresistant neuroblastoma cell line with the antimalarial ozonide OZ513

Treatment of a chemoresistant neuroblastoma cell line with the antimalarial ozonide OZ513

Toxic Optic Neuritis due to Isotretinoin in a Child with Neuroblastoma: A Case Report

The “neuro” of neuroblastoma: Neuroblastoma as a neurodevelopmental disorder

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